Adenine nucleotide translocase is involved in a mitochondrial coupling defect in MFN2-related Charcot–Marie–Tooth type 2A disease

Charcot–Marie–Tooth type 2A disease (CMT2A), a dominantly inherited peripheral neuropathy, is caused by mutations in MFN2, a mitochondrial fusion protein. Having previously demonstrated a mitochondrial coupling defect in CMT2A patients’ fibroblasts, we here investigate mitochondrial oxygen consumption and the expression of adenine nucleotide translocase (ANT) and uncoupling proteins from eight other patients with the disease. The mitochondrial uncoupling was associated with a higher respiratory rate, essentially involving complex II proteins. Furthermore, a twofold increase in the expression of ANT led to the reduced efficiency of oxidative phosphorylation in CMT2A cells, suggesting that MFN2 plays a role in controlling ATP/ADP exchanges.     

Adrenomedullin 2/Intermedin in the Hypothalamo–Pituitary–Adrenal Axis

Adrenomedullin 2/intermedin (AM2/IMD) is a new member of the calcitonin/calcitonin gene-related peptide (CGRP) family. CGRP, adrenomedullin (AM), and AM2/IMD share the receptor system consisting of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMP). The CRLR/RAMP2 or CRLR/RAMP3 complex forms the AM receptor, whereas the CRLR/RAMP1 forms the CGRP receptor. AM2/IMD binds non-selectively to all three CRLR/RAMP complexes. AM2/IMD has various actions, such as a potent vasodilator action and a protective action against oxidative stress, like AM and CGRP. When administered intracerebroventricularly, AM2/IMD stimulates the sympathetic nervous system and increases blood pressure. In human hypothalamus, AM2/IMD is expressed in the paraventricular and supraoptic nuclei and colocalized with arginine vasopressin. Anterior pituitary cells were diffusely immunostained for AM2/IMD. AM2/IMD stimulates the release of ACTH, prolactin, and oxytocin, but suppresses GH release. Some of these pituitary actions of AM2/IMD have been supposed to be mediated by an unidentified unique receptor for AM2/IMD. In the adrenal gland, immunoreactive (IR)-AM2/IMD and IR-AM were detected in the medulla, while the degree of IR-AM2/IMD and IR-AM in the cortex was relatively weak or undetectable. Furthermore, AM2/IMD and AM were expressed in adrenocortical tumors, such as aldosterone-secreting adenomas, and pheochromocytomas. CRLR and RAMPs are expressed in the hypothalamus, pituitaries, adrenal glands, and adrenal tumors. Thus, AM2/IMD is expressed in every endocrine organ of the hypothalamo–pituitary–adrenal axis together with its receptor. AM2/IMD may act as a neurotransmitter or modulator in the brain and as a paracrine/autocrine regulator in the hypothalamo–pituitary–adrenal axis.     

Action–perception coupling in kinesthesia: A new approach

According to recent findings, intentional motor actions are controlled by resetting the referent position, R, at which neuromuscular elements, including reflexes, begin to act. It is suggested that somatosensory afferents inform the brain about the deviation (P) of body segments from the centrally set referent position. To perceive the actual position (Q) of body segments and form the position sense (PS), the central and afferent signals are combined: Q=R+P. In previous studies, the R has been shown to remain invariant during involuntary changes in the wrist position elicited by sudden unloading of muscles, suggesting that only the afferent component is responsible for the PS during this reflex. In contrast, the central PS component, R, is predominantly responsible for PS during intentional motion in isotonic conditions. We tested the hypothesis that the R and P are interchangeable PS components such that involuntary changes in wrist position elicited by the unloading reflex can easily be reproduced by making intentional changes in wrist position in isotonic conditions, in the absence of vision. The PS rule also suggests that PS is independent of sense of effort, which was tested by asking subjects to reproduce elbow joint angles under different constant loads. We also tested the hypothesis that tendon vibration may elicit motion that may not be perceived by subjects (no-motion illusion). These hypotheses were confirmed in three experiments. It is concluded that the R and P are additive components of PS and that, contrary to the conventional view, PS is independent of the sense of effort or efference copy. The PS rule also explains kinesthetic illusions and the phantom limb phenomenon. This study advances the understanding of action–perception coupling in kinesthesia.     

Opioid system genes in alcoholism: A case–control study in Croatian population

Due to their involvement in dependence pathways, opioid system genes represent strong candidates for association studies investigating alcoholism. In this study, single nucleotide polymorphisms within the genes for mu (OPRM1) and kappa (OPRK1) opioid receptors and precursors of their ligands – proopiomelanocortin (POMC), coding for beta-endorphin and prodynorphin (PDYN) coding for dynorphins, were analyzed in a case–control study that included 354 male alcohol-dependent and 357 male control subjects from Croatian population. Analysis of allele and genotype frequencies of the selected polymorphisms of the genes OPRM1/POMC and OPRK1/PDYN revealed no differences between the tested groups. The same was true when alcohol-dependent persons were subdivided according to the Cloninger’s criteria into type-1 and type-2 groups, known to differ in the extent of genetic control. Thus, the data obtained suggest no association of the selected polymorphisms of the genes OPRM1/POMC and OPRK1/PDYN with alcoholism in Croatian population.     

Personality profile in essential tremor: A case–control study

BackgroundNeuropsychiatric findings described in essential tremor (ET) include depression and anxiety. There may be personality features as well; in 2004, we demonstrated higher harm avoidance (HA) scores in ET patients than controls. We now (1) determined whether this finding could be replicated in a new sample of cases and controls, and (2) analyzed HA sub-scores (HA1?HA4) to further understand case–control differences.Design/Methods60 ET cases and 35 controls were evaluated using the Tridimensional Personality Questionnaire (TPQ), which assesses three domains of personality: HA, novelty seeking (NS), and reward dependence (RD).ResultsTotal HA and total NS scores were marginally higher in cases than controls (14.8 ± 7.6 vs. 12.4 ± 5.3, p = 0.09) and (13.8 ± 5.4 vs. 11.8 ± 4.9, p = 0.09), respectively. When adjusted for age and gender, cases and controls differed with respect to total HA score (p = 0.03) but not total NS score (p = 0.10). Further analysis of HA sub-scores demonstrated that HA1 (anticipatory worry and pessimism) and HA4 (fatigability and asthenia) were most robustly elevated in cases vs. controls (p = 0.04 and p = 0.01, respectively).ConclusionsThis study suggests that ET cases have a personality profile characterized by a greater HA, with certain domains of HA most affected. It is unclear whether this personality profile is pre-morbid or is a co-morbid feature of the illness, nor it is known whether the greater tendency towards HA in ET lessens receptivity to deep brain stimulation surgery and other therapies.     

A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot–Marie–Tooth disease type 2L

Charcot–Marie–Tooth disease (CMT) is a group of clinically and genetically heterogeneous peripheral neuropathies. HSPB8 gene encodes heat shock protein 22 (HSP22) which belongs to the superfamily of small stress induced proteins. Mutations in HSPB8 are implicated to CMT2L and distal hereditary motor neuropathy 2A (dHMN2A). All three reported HSPB8 mutations are interestingly located in the Lys141 residue. In the present study, we examined a Korean axonal CMT patient who presented distal limb atrophy, sensory loss, areflexia, and axonal loss of large myelinated fibers. Whole exome sequencing identified a novel missense mutation c.422A>C (p.Lys141Thr) in HSPB8 as the underlying cause of the CMT2 patient. The mutation was regarded as a de novo case because both unaffected parents have no such mutation. The patient with HSPB8 mutation is the first case in Koreans. Clinical heterogeneities have been revealed in patients with Lys141 mutation; the present patient revealed similar phenotype of CMT2L. In addition, the lower limb MRI revealed a similarity between our HSPB8 and HSPB1 patients. It seems that the Lys141 site in the alpha-crystallin domain of HSPB8 is regarded as a mutational hot spot for peripheral neuropathy development, and mutations even in the same codon can exhibit different CMT phenotypes.     

A systematic review of multisensory cognitive–affective integration in schizophrenia

The etymology of schizophrenia implies poor functional integration of sensory, cognitive and affective processes. Multisensory integration (MSI) is a spontaneous perceptual–cognitive process by which relevant information from multiple sensory modalities is extracted to generate a holistic experience. Deficits in MSI may hinder prompt and appropriate behavioural responses in a complex and transient environment. Despite extensive investigation of sensory, cognitive and affective processing in patients with schizophrenia, little is known about how MSI is affected in the illness. We systemically searched the PubMed electronic database and reviewed twenty-nine behavioural and neuroimaging studies examining MSI in patients with schizophrenia. The available evidence indicates impaired MSI for non-emotional stimuli in schizophrenia, especially for linguistic information. There is also evidence for altered MSI for emotional stimuli, although findings are inconsistent and may be modality-specific. Brain functional alterations in the superior temporal cortex and inferior frontal cortex appear to underlie the deficits in both non-emotional and emotional MSI. The limitations of the experimental paradigms used and directions for future research are also discussed.     

Childhood medulloblastoma in Denmark 1960–1984 A population-based retrospective study

Medulloblastoma is a common paediatric brain tumour, located in the cerebellum and in the IV ventricle, surpassed in frequency only by astrocytomas. 180 children below the age of 15 with a medulloblastoma of the posterior fossa were treated in Denmark in the 25-year period from 1960 to 1984 and followed up until the end of 1996, or until death. During the 25 years they accounted for 20% of all intracranial tumours in children in Denmark. All tumours were histologically verified. The mean annual incidence was 6.4×10^–6, decreasing slightly with a factor of 0.12×10^–6 per year. The male/female ratio was 2.1 – twice that of the background population of children (1.05). The 5-year survival rate following diagnosis, surgery and radiotherapy was 23%, and the 25-year survival rate was 16%. The 5-year survival rate was 8% in the first 5-year period of 1960–1964, increasing to 36% in the last period 1980–1984. Presumably the increase in survival depends on many factors, e.g. improved diagnostic methods and neuroanaesthesia, better operative technique (microscope), improvements in radiotherapy and the introduction of chemotherapy. The best predictive factors of a good prognosis were preoperative CSF shunting, radical tumour removal and complete radiotherapy, i.e. irradiation of the brain, tumour bed and spinal cord. The survival rate in the last five-year period was seven times higher than the survival rate found in a comparable Danish study from the years 1935–1959. Most of the children followed Collins law of risk index. The results of treatment in children with medulloblastoma remain unsatisfactory. Accordingly, participation in international prospective studies of multimodal treatment should be encouraged, possibly using chemotherapy prior to surgery.     

5HT–2C receptor polymorphism in suicide victims

Abstract. Sustainable observations suggest that suicidal behaviour by itself may have biological correlates, among which those related to the serotonergic synapse hold the key position. Based on the association of suicide and serotonergic dysfunction, it was proposed that genetic mechanisms affecting suicidal behaviour could be related to the alterations of the genes encoding the elements of 5HT synapse. The present study tested the association of the polymorphism in the serotonin 2C (5HT-2C) receptor coding region (Cys23Ser) with suicide commitment. Study was based on two independent samples, one of German (284 suicide victims versus 297 controls) and other of Slavic/Croatian (118 suicide victims versus 275 controls) ethnicity. No significant differences in allele or genotype frequencies between victims and controls were demonstrated. Results did not provide supporting evidence for the potential involvement of the investigated variants of 5HT-2C receptor in the susceptibility to suicide.     

A longitudinal VBM study in paediatric obsessive–compulsive disorder at 2-year follow-up after cognitive behavioural therapy

Objectives. To identify neurodevelopmental differences in regional brain volume between medication-free paediatric obsessive–compulsive disorder (OCD) patients and controls at 2-year follow-up after cognitive behavioural therapy. Methods. We assessed 17 medication-free paediatric OCD patients (mean age 13.8 years; SD = 2.8; range 8.2–19.0) and 20 controls, matched on age and gender, with T1-weighted MR scans in a repeated measures design at three time points with intervals of 6 months and 2 years. Voxel based morphometry (VBM) was used to test whole brain voxel-wise for the effects of diagnosis and time on regional grey matter (GM) and white matter volumes. Results. GM volume of the orbitofrontal cortex showed a group × time interaction effect, driven by an increase of GM volume over the whole time period in OCD patients and a decrease in controls. When splitting the groups in two age groups (8–12 and 13–19 years) this interaction effect was only seen in the youngest age group. Conclusions. Neuroimaging findings in paediatric OCD after 6 months of CBT in the GM volume of the orbital frontal cortex are still present at 2-year follow-up.     

A Multivariate Model of Parent–Adolescent Relationship Variables in Early Adolescence

Given the importance of predicting outcomes for early adolescents, this study examines a multivariate model of parent–adolescent relationship variables, including parenting, family environment, and conflict. Participants, who completed measures assessing these variables, included 710 culturally diverse 11–14-year-olds who were attending a middle school in a Southeastern state. The parents of a subset of these adolescents (i.e., 487 mother–father pairs) participated in this study as well. Correlational analyses indicate that authoritative and authoritarian parenting, family cohesion and adaptability, and conflict are significant predictors of early adolescents’ internalizing and externalizing problems. Structural equation modeling analyses indicate that fathers’ parenting may not predict directly externalizing problems in male and female adolescents but instead may act through conflict. More direct relationships exist when examining mothers’ parenting. The impact of parenting, family environment, and conflict on early adolescents’ internalizing and externalizing problems and the importance of both gender and cross-informant ratings are emphasized.     

A quantitative analysis of facial emotion recognition in obsessive–compulsive disorder

Obsessive–Compulsive Disorder (OCD) is characterized by persistent and unwanted obsessions generally accompanied by ritualistic behaviors or compulsions. Previous research proposed specific disgust facial emotion recognition deficits in patients with OCD. This research however, remains largely inconsistent. Therefore, the results of 10 studies contrasting facial emotion recognition accuracy in patients with OCD (n=221) and non-psychiatric controls (n=224) were quantitatively reviewed and synthesized using meta-analytic techniques. Patients with OCD were less accurate than controls in recognizing emotional facial expressions. Patients were also less accurate in recognizing negative emotions as a whole; however, this was largely due to significant differences in disgust and anger recognition specifically. The results of this study suggest that patients with OCD have difficulty recognizing specific negative emotions in faces and may misclassify emotional expressions due to symptom characteristics within the disorder. The contribution of state-related emotion perception biases to these findings requires further clarification.